rs267607508

chr17-44908128-G-Achr17-44908128-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3 PP5

The NM_002055.5(GFAP):c.1193C>T(p.Ser398Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S398Y) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GFAP NM_002055.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.40

Genes affected

GFAP (HGNC:4235): (glial fibrillary acidic protein) This gene encodes one of the major intermediate filament proteins of mature astrocytes. It is used as a marker to distinguish astrocytes from other glial cells during development. Mutations in this gene cause Alexander disease, a rare disorder of astrocytes in the central nervous system. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a region_of_interest Tail (size 54) in uniprot entity GFAP_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_002055.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.781
• PP5: Variant 17-44908128-G-A is Pathogenic according to our data. Variant chr17-44908128-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 190363.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GFAP	NM_002055.5	c.1193C>T	p.Ser398Phe	missense_variant	8/9	ENST00000588735.3
GFAP	NM_001363846.2	c.1313C>T	p.Ser438Phe	missense_variant	9/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GFAP	ENST00000588735.3	c.1193C>T	p.Ser398Phe	missense_variant	8/9	1	NM_002055.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Alexander disease Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

GeneReviews

Jan 08, 2015

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D;D;T;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.78	D;D;D;D;D
MetaSVM	Pathogenic	0.83	D
MutationTaster	Benign	0.96	D;D
PrimateAI	Uncertain	0.62	T
Polyphen		0.86	.;P;.;.;.
MutPred		0.59		Loss of disorder (P = 0.0174);Loss of disorder (P = 0.0174);.;.;.;
MVP		0.99
ClinPred		0.85	D
GERP RS		5.2
Varity_R		0.24
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs267607508; hg19: chr17-42985496;